1. Review the clinical indications for a chromosome analysis (p.385-336)
Prenatal
Amniotic fluid or CVS analysis in mothers presenting with advanced maternal age (greater than 35 yrs), an ultrasound detected anomaly, abnormal quad marker screen, or parents with a history of genetic problems.
Couples with two or more fetal losses
Couples with infertility problems
Abortuses and malformed stillborns
Postnatal
To rule out classical chromosome syndromes
Individuals with unexplained mental retardation
Patients with multiple congenital anomalies
Siblings of a known carrier of a chromosome abnormality
Parents of a child with a chromosome abnormality
Individuals with ambiguous genitalia
Females iwth amenorrhea; pubertal failure in males and females
Neoplasia
Preleukemic conditions, leukemia, lymphoma, and solid tumors
2. Categorize the severity of possible phenotypic outcomes as they related to the spectrum of genetic imbalances that can occur in chromosome abnormalities (p.387)
The larger the genetic imbalance, the more devestating the result and the earlier the miscarriage.
Large genetic imbalance
Devestating of blastogenesis
Transient implantation, implantation, or nonimplantation of conceptus
Stillbirth or early neonatal death to some extrauterine survival
Smaller or no genetic imbalance
Moderate to mild distortion of intrauterine development
Substantial extrauterine survival; minimal or no discernible phenotypic effects
3. Review the concept of polyploidy, specifically triploidy, and differentiate the clinical manifestations observed when the extra haploid chromosome set is maternally or paternally inherited; describe how the concept of genetic imprinting relates to human development. (p.388-390)
Polyploidy refers to changes in chromosome number where entire genome can be duplicated; in triploidy, there are three copies of every chromosome.
The parental origin of the extra set of haploid chromosomes results in different clinical maneifestations. When the extra set is paternal, the placenta is abnormally large with partially hydatidiform moles. When the extra set is maternal, the placenta is much smaller than the fetus and the fetus exhibits macrocephaly and fusion of fingers and toes. The maternal and paternal contributions to the development of hte embryo are not the same but both are necessary for normal development.
Genomic imprinting is set into the maternal and paternal gamates so that certain alleles are active in one parental gamate contribution, but not the other. Maternal contributions appear to be more important for the embryo while paternal contributions appear to be more important for development of the placenta and membranes.
4. Describe the clinical significance of aneuploidy and the pathogenetic mechanisms underlying nondisjunction. (p.390-392)
Aneuploidy occures in 3-4% of all clinically recognized pregnancies though most autosomal aneuploidies are incompatible with fetals survival and observes most frequently in miscarages.
Chromosomal trisomies have been reported in miscarriages for all chromosomes; Aneuploidy of gene rich chromosomes (1, 3, 6, 11, 12, 17, 19, and 22) result in a high genetic imbalance and is not compatible with survival while aneuploidy of gene poor chromsomes (8, 9 as mosaics and 13, 18, and 21) can be see in live births. Autosomal monosomies are extremely rare in both livebirths and recognized abortuses.
The most common cause of aneuploidy is chromosomal non-disjunction which can occur during meiosis I or meiosis II where chromosomes fail to segregate properly during meiotic divisions. If the extra chromosomes are heterozygous pairs, the trisomy originated from meiosis I non-disjunction; if the extra chromosomes are homologous pairs, the trisomy originated from meiosis II non-disjunction. An egg that has non-disjunction during meiosis II can still have a chance of producing normal gamates.
5. Describe the clinical features of down syndrome, patau syndrome, and edwards syndrome. (p.397-399)
Down Syndrome
Trisomy 21
Incidence: 1/700 births
Mental retardation
Epicanthic folds
Flat facial profile
Congenital heart defects
Intestinal stenosis
Umbilical hernia
Predisposition to leukemia
Hypotonia
Gap between first and second toe
Beta-amoloid is overproduced
Similar symptomes as Alzheimer's disease with myofibrillary tangles and dementia
Patau Syndrome
Trisomy 13
Incidence: 1/15,000 births
Microphthalmia
Polydactyly
Microcenphaly
Mental retardation
Cleft lip/palate
Cardiac defects
Umbelical hernia
Renal defects
Rocker-bottom feet
Edward's Syndrome
Trisomy 18
Incidence: 1/8,000 births
Prominent Occiput
Mental Retardation
Micrognathia
Low set ears
Short neck
Overlapping fingers
Congenital heart defects
Renal malformations
Limited hip abduction
Rocker bottom feet
6. Describe the concept of aberrant chromosome segregation of both a parental balanced reciprocal translocation and robertsonian translocation and their related clinical outcomes (p.405-407)
Abbrent chromosomal rearrangements can break chromosmes and reattach incorrectly. Balanced reciprocal translocations are when two chromosomes break and are recipocally reattached but no genetic material is lost; this results in the individual being phenotypically normal. If this individual should have a child, there would be no problem if he should pass on two normal chromosomes. If he passes on two abnormal chromosomes, the child will also be normal phenotypically but be a carrier. However, if he passes on one normal and one abnormal chromosome, there is not a complete set of genetic information and a partial trisomy will result.
Robersonian translocations are the fusion of acrocentric chromosomes. The short arms of acrocentric chromosomes usually code for the same thing (rRNA genes) so the loss of genetic information can be tolerated.
7. Review the features of segmental aneusomy syndromes and discribe how fluorescence in situ hybridization (FISH) is used in the clinical cytogenetics laboratory to confirm the diagnosis of these genetic disorders. (p.408,413)
Segmental aneusomal syndromes commonly have duplications or deletions of small chromosomal segments containing few genes that are functionally related, but by chance are closely linked on the crhomsome. Phenotype tends to be variable because of different possible break points and the occurence is usualyl sporadic but may cluster in families.
The pathogenic mechanism responsible for microdeletion and microduplication syndromes involves unequal crossing over between misaligned siter chromatids or homologous chromsomes containing homologous copies of a repeated DNA sequence.
FISH is a physical DNA mapping technique in qhich a DNA proble labeled with a marker molecule is hybridized to chromosomes on a slide an visualized using UV light. This technique can be used to detect submicroscopic deletions, additonal chromosomal material, and cryptic translocations. FISH can also be ued to identify marker chromomosomes, and detect minimal residual disease in neoplasia, prenatal aneuploidy, and subtelomeric rearrangements in idiopatic mental retardation.
8. Describe the principles of X-inactivation and the clinical consequences associated with skewed X-inactivation. (p.414, 415)
In somatic cells of females, only one X chromosome is active transcriptionally to allow for dosage compensation. The second chromosome is condensed and inactive in interphase nuclei and is called a barr body. Inactivation occures in the blastocyst stage and is random for paternal and maternal X-chromosomes and is permenent in somatic tissues
X-inactivation is initiated at the X-inactivation center on Xq13. XIST gene is only expressed from the inactive X and inactivation occurs through DNA methylation. Muatations in the XIST gene can lead to abnormal phenotype.
65% if genes are completely inactivated; 15% of genes completely escape inactivation and are epxressed; 20% of genes are inactivated in some cells and activated in others. More Xp genes escape inactivations than Xq and may partly explain why Xp deletions are more severe than Xq deletions.
5-10% of normal females demonstrate extreme skewing of inactivation pattern. For x-linked disorders, unfortunate Lyonization may produce expression of a disease phenotype. Skewed X-inactivation occures in both balanced and unbalanced X and autosomal translocations.
9. Review the clincal features of Klinefelter and Turner syndromes. (p.416, 417)
Klinefelter Syndrome
47, XXY
Incidence: 1/1,000 newborn males
Normal face (gee thanks...thats so helpful)
Tendency towards long arms and legs
Small genitalia
Abnormal breast development (gynecomastia)
IQ usually normal but IQ of some less than 80
Infertility
Turner Syndrome
45, X
Short stature
Low posterior hairline
Webbing of neck
Coactation of aorta
Broad chest and widely spaced nipples
Cubitus valgus
Streak ovaries
Infertility
Amenorrhea
Pigmented nevi
Peripheral lymphedema at birth
10. Describe sex chromosome abnormalities that can result in sex reversal phenotypes.
Objectives
1. Review the clinical indications for a chromosome analysis (p.385-336)
Prenatal
Postnatal
Neoplasia
2. Categorize the severity of possible phenotypic outcomes as they related to the spectrum of genetic imbalances that can occur in chromosome abnormalities (p.387)
The larger the genetic imbalance, the more devestating the result and the earlier the miscarriage.
3. Review the concept of polyploidy, specifically triploidy, and differentiate the clinical manifestations observed when the extra haploid chromosome set is maternally or paternally inherited; describe how the concept of genetic imprinting relates to human development. (p.388-390)
Polyploidy refers to changes in chromosome number where entire genome can be duplicated; in triploidy, there are three copies of every chromosome.
The parental origin of the extra set of haploid chromosomes results in different clinical maneifestations. When the extra set is paternal, the placenta is abnormally large with partially hydatidiform moles. When the extra set is maternal, the placenta is much smaller than the fetus and the fetus exhibits macrocephaly and fusion of fingers and toes. The maternal and paternal contributions to the development of hte embryo are not the same but both are necessary for normal development.
Genomic imprinting is set into the maternal and paternal gamates so that certain alleles are active in one parental gamate contribution, but not the other. Maternal contributions appear to be more important for the embryo while paternal contributions appear to be more important for development of the placenta and membranes.
4. Describe the clinical significance of aneuploidy and the pathogenetic mechanisms underlying nondisjunction. (p.390-392)
Aneuploidy occures in 3-4% of all clinically recognized pregnancies though most autosomal aneuploidies are incompatible with fetals survival and observes most frequently in miscarages.
Chromosomal trisomies have been reported in miscarriages for all chromosomes; Aneuploidy of gene rich chromosomes (1, 3, 6, 11, 12, 17, 19, and 22) result in a high genetic imbalance and is not compatible with survival while aneuploidy of gene poor chromsomes (8, 9 as mosaics and 13, 18, and 21) can be see in live births. Autosomal monosomies are extremely rare in both livebirths and recognized abortuses.
The most common cause of aneuploidy is chromosomal non-disjunction which can occur during meiosis I or meiosis II where chromosomes fail to segregate properly during meiotic divisions. If the extra chromosomes are heterozygous pairs, the trisomy originated from meiosis I non-disjunction; if the extra chromosomes are homologous pairs, the trisomy originated from meiosis II non-disjunction. An egg that has non-disjunction during meiosis II can still have a chance of producing normal gamates.
5. Describe the clinical features of down syndrome, patau syndrome, and edwards syndrome. (p.397-399)
Down Syndrome
Patau Syndrome
Edward's Syndrome
6. Describe the concept of aberrant chromosome segregation of both a parental balanced reciprocal translocation and robertsonian translocation and their related clinical outcomes (p.405-407)
Abbrent chromosomal rearrangements can break chromosmes and reattach incorrectly. Balanced reciprocal translocations are when two chromosomes break and are recipocally reattached but no genetic material is lost; this results in the individual being phenotypically normal. If this individual should have a child, there would be no problem if he should pass on two normal chromosomes. If he passes on two abnormal chromosomes, the child will also be normal phenotypically but be a carrier. However, if he passes on one normal and one abnormal chromosome, there is not a complete set of genetic information and a partial trisomy will result.
Robersonian translocations are the fusion of acrocentric chromosomes. The short arms of acrocentric chromosomes usually code for the same thing (rRNA genes) so the loss of genetic information can be tolerated.
7. Review the features of segmental aneusomy syndromes and discribe how fluorescence in situ hybridization (FISH) is used in the clinical cytogenetics laboratory to confirm the diagnosis of these genetic disorders. (p.408,413)
Segmental aneusomal syndromes commonly have duplications or deletions of small chromosomal segments containing few genes that are functionally related, but by chance are closely linked on the crhomsome. Phenotype tends to be variable because of different possible break points and the occurence is usualyl sporadic but may cluster in families.
The pathogenic mechanism responsible for microdeletion and microduplication syndromes involves unequal crossing over between misaligned siter chromatids or homologous chromsomes containing homologous copies of a repeated DNA sequence.
FISH is a physical DNA mapping technique in qhich a DNA proble labeled with a marker molecule is hybridized to chromosomes on a slide an visualized using UV light. This technique can be used to detect submicroscopic deletions, additonal chromosomal material, and cryptic translocations. FISH can also be ued to identify marker chromomosomes, and detect minimal residual disease in neoplasia, prenatal aneuploidy, and subtelomeric rearrangements in idiopatic mental retardation.
8. Describe the principles of X-inactivation and the clinical consequences associated with skewed X-inactivation. (p.414, 415)
In somatic cells of females, only one X chromosome is active transcriptionally to allow for dosage compensation. The second chromosome is condensed and inactive in interphase nuclei and is called a barr body. Inactivation occures in the blastocyst stage and is random for paternal and maternal X-chromosomes and is permenent in somatic tissues
X-inactivation is initiated at the X-inactivation center on Xq13. XIST gene is only expressed from the inactive X and inactivation occurs through DNA methylation. Muatations in the XIST gene can lead to abnormal phenotype.
65% if genes are completely inactivated; 15% of genes completely escape inactivation and are epxressed; 20% of genes are inactivated in some cells and activated in others. More Xp genes escape inactivations than Xq and may partly explain why Xp deletions are more severe than Xq deletions.
5-10% of normal females demonstrate extreme skewing of inactivation pattern. For x-linked disorders, unfortunate Lyonization may produce expression of a disease phenotype. Skewed X-inactivation occures in both balanced and unbalanced X and autosomal translocations.
9. Review the clincal features of Klinefelter and Turner syndromes. (p.416, 417)
Klinefelter Syndrome
Turner Syndrome
10. Describe sex chromosome abnormalities that can result in sex reversal phenotypes.